Rheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation and
bone destruction as the result of increased numbers and activity of osteoclasts. RA is often associated with
metabolic syndrome, whereby elevated levels of LDL are oxidized into oxLDL, which might affect osteoclastogenesis.
In this study, we induced antigen-induced arthritis (AIA) in Apoe−/− mice, which spontaneously develop
high LDL levels, to investigate the effects of high LDL/oxLDL levels on osteoclast differentiation and bone
destruction. Whereas basal levels of bone resorption were comparable between naive WT and Apoe−/− mice,
induction of AIA resulted in a significant reduction of bone destruction in Apoe−/− mice as compared to WT
controls. In line with that, the TRAP+ area on the cortical bone was significantly decreased. The absence of Apoe
did affect neither the numbers of CD11b+Ly6Chigh and CD11b−/Ly6Chigh...
Show moreRheumatoid arthritis (RA) is a chronic inflammatory disease, characterized by severe joint inflammation and
bone destruction as the result of increased numbers and activity of osteoclasts. RA is often associated with
metabolic syndrome, whereby elevated levels of LDL are oxidized into oxLDL, which might affect osteoclastogenesis.
In this study, we induced antigen-induced arthritis (AIA) in Apoe−/− mice, which spontaneously develop
high LDL levels, to investigate the effects of high LDL/oxLDL levels on osteoclast differentiation and bone
destruction. Whereas basal levels of bone resorption were comparable between naive WT and Apoe−/− mice,
induction of AIA resulted in a significant reduction of bone destruction in Apoe−/− mice as compared to WT
controls. In line with that, the TRAP+ area on the cortical bone was significantly decreased. The absence of Apoe
did affect neither the numbers of CD11b+Ly6Chigh and CD11b−/Ly6Chigh osteoclast precursors (OCPs) in the BM
of naïve mice nor their in vitro osteoclastogenic potential as indicated by comparable mRNA expression of
osteoclast markers. Addition of oxLDL, but not LDL, to pre-osteoclasts from day 3 and mature osteoclasts from
day 6 of osteoclastogenesis strongly reduced the number of TRAP+ osteoclasts and their resorptive capacity. This
coincided with a decreased expression of various osteoclast markers. Interestingly, oxLDL significantly lowered
the expression of osteoclast-associated receptor (Oscar) and the DNAX adaptor protein-12 encoding gene Tyrobp,
which regulate the immunoreceptor tyrosine-based activation motif (ITAM) co-stimulation pathway that is
strongly involved in osteoclastogenesis. Collectively, our findings suggest that under inflammatory conditions in
the joint, high LDL levels lessen bone destruction during AIA, probably by formation of oxLDL that inhibits
osteoclast formation and activity through modulation of the ITAM-signaling.
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